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Biomedical subjects

J M Poirier

Publications and source records attributed to J M Poirier.

At least 37 records · Page 2Linked to original sources
PubMed1997

Plasma itraconazole concentrations in patients with neutropenia: advantages of a divided daily dosage regimen.

A group of 36 patients in the hematology department of Saint-Antoine Hospital, Paris, France, was on chemotherapy. The patients were also given antiacid drugs to prevent gastrointestinal toxicity and itraconazole as prophylaxis against aspergillosis. The antifungal drug was given as 100-mg capsules three times a day shortly after meals. The plasma itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography at steady state. Of 36 patients, 29 (81%) had adequate plasma itraconazole concentrations (> or = 250 ng/ml) after 8 +/- 2 days. The 7 patients with low plasma itraconazole concentrations were given 200 mg three times a day. Of the 36 patients, 34 (94%) had effective plasma concentrations within 2 weeks of the beginning of treatment. The two remaining patients were lost to follow-up. The proposed itraconazole regimen provides effective prophylaxis against aspergillosis and represents a substantial economic advantage over a single daily dose of 400 to 600 mg. The marked intrapatient and interpatient variations in plasma itraconazole indicate the need for regular therapeutic drug monitoring to ensure effective plasma itraconazole concentrations in all neutropenic patients.

Adolescent↗
PubMed1997

Epidemiological aspects of diabetes in Cameroon: what is the role of tropical diabetes?

Diabetes is a worldwide public health problem made more acute in Africa by low socio-economic standards. Cases with an unusual clinical course are frequent and probably related to tropical diabetes, a syndrome that has not yet been precisely defined. This study reports the results of a prospective study carried out in Cameroon on 550 diabetic patients attending the Yaounde Central Hospital who were followed between December 1990 and July 1994. They were classified according to WHO criteria into 136 insulin-dependent diabetes mellitus (IDDM) (24.7%), 405 non-insulin- dependent diabetes mellitus (NIDDM) (73.7%) and 9 diabetes secondary to other diseases (1.6%). No cases of malnutrition-related diabetes mellitus (MRDM) were found, but 18 subjects were considered to have so-called "African diabetes". Investigation of the cohort showed epidemiological and clinical features markedly different from those of Caucasian diabetic subjects. The age of onset in IDDM occurred in all age groups, with a mean (+/- SD) close to that of NIDDM (40.9 +/- 4.8 years vs 49 +/- 10.9; P < 0.001). A clear male preponderance was found (M/F sex ratio = 1.63), as it has been reported in most studies from sub-Saharan Africa, in contrast with the slight female predominance noted in the Sahel and Saharan countries. An increased prevalence of young and non-obese NIDDM was also found. Seventy-nine NIDDM cases (19.5%) were detected in individuals under 40 years of age, including 31 with normal weight. Many atypical features were noted: IDDM in obese patients, NIDDM in ketotic subjects and patients with varying insulin requirements, all of which led to difficulties in classifying many diabetic patients according to current practices. All these uncommon features are concordant with the nature of tropical diabetes, including not only MRDM but also African diabetes which occurs in individuals older than MRDM patients who show no signs of malnutrition. Thus, tropical diabetes is apparently a syndrome with aetiological heterogeneity which requires further definition through clinical, genetic and immunological studies.

Adult↗
PubMed1996

Cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in the conscious dog.

We studied the cardiac electrophysiological effects of propafenone and its 5-hydroxylated metabolite in conscious dogs. Sinus rate, corrected sinus recovery time and Wenckebach point were measured in 6 intact dogs. Atrial rate, ventricular rate and atrial effective refractory period were measured in 6 atrioventricular-blocked dogs. In both groups, we also determined blood pressure and plasma drug concentrations. Each dog received, with at least an 8-day interval, propafenone (hydrochloride) and 5-hydroxypropafenone (hydrochloride) in 4 successive intravenous injections, 30 min apart, at 0.5, 0.5, 1 and 2 mg kg(-1). Propafenone increased sinus rate and atrial rate more markedly than 5-hydroxypropafenone, and also transiently ventricular rate, whereas 5-hydroxypropafenone decreased it weakly. Propafenone shortened corrected sinus recovery time and increased Wenckebach point at the highest dose only, whereas 5-hydroxypropafenone did not modify corrected sinus recovery time and increased Wenckebach point less markedly than propafenone. Both drugs produced an identical atrial effective refractory period lengthening. Propafenone either increased mean blood pressure (in intact dogs) or decreased it (in atrioventricular-blocked dogs) at the highest dose only, whereas 5-hydroxypropafenone did not produce any effect on this parameter. Overall, these results show that propafenone and 5-hydroxypropafenone exhibit cardiac electrophysiological effects, reflecting (a) direct vagolytic action for both drugs associated with cardiodepressant effects for 5-hydroxypropafenone, and (b) marked atrial antiarrhythmic properties for 5-hydroxypropafenone probably involved in the therapeutic effect of propafenone.

Animals↗
PubMed1996

[Value of video-assisted thoracic surgery in internal medicine. Apropos of 7 cases].

Since a few years, the medical thoracoscopy has already been used specially for the diagnostic and therapeutic taking up of the pleural pathology. Behind it, the video-assisted thoracic surgery has been improved since 1990. As a surgical technology, it proved its interest refering to the classical thoracotomy by lessening operative morbidity and mortality. The authors discuss its main indications about seven cases, recruted in the internal medicine service and operated in the thoracic surgery service of the Val-de-Grâce hospital. Some of these indications are now admited by most of the authors: 1) diagnostic aims: pulmonary biopsy in case of interstitial pathology, of pulmonary peripheral under-pleural nodule and sometimes of solid tumors of the mediastinum, specially of some lymph-nodes. 2) Therapeutic aims: the spontaneous pneumothorax treatment of the adult remains the most classical indication; the thoracic sympathectomy, the creation of pleuropericardial windows and the resection of benign tumors of the mediastinum are now well acknowledged indications.

Humans↗
PubMed1996

[Development of blood pressure level over a three years period in non-insulin dependent diabetic subjects according to their microalbuminuria].

UNLABELLED: The purpose of this study is to compare over a three year period blood pressure modifications of type 2 diabetic subjects who suffer of incipient nephropathy to those who remain unharmed of this complication. PATIENTS AND METHOD: This study population is composed of 83 normotensive (BP < 140/90 mmHg) type 2 diabetic patients not receiving cardio-vascular treatment and unharmed of nephropathy (microalbuminuria inferior to 30 mg/24 hours). An evaluation of the diabetes mellitus is undertaken at a three year interval (A0 and A3). These 83 subjects are distributed in two groups according to the 24 hours microalbuminuria rate at A3. In group I (n = 60), patients whose rate is lower than 30 mg/24 hours and in group II (n = 23), patients whose microalbuminuria is over 30 mg. For these two groups, the following elements are compared at A0 and A3: body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), serum creatinine, cholesterol and triglycerides. RESULTS: The two groups do not differ in age (57.1 +/- 12 vs 53.8 +/- 16.4 years), duration of diabetes mellitus (11.7 +/- 8.6 vs 13.3 +/- 10.4 years) or body mass index (25.9 +/- 3.8 vs 26.2 +/- 4 kg/m2). At the time of the initial evaluation at A0, none of the studied parameters shows a significant difference between the two populations. Comparison of statements undertaken at A3 shows that blood pressure of Group II patients is higher than in group I, but the difference is only significant for systolic blood pressure (132 +/- 12 vs 139 +/- 11 mmHg; p < 0.01). The balance of diabetes mellitus, serum creatinine and lipid levels do not differ between these two groups. The blood pressure level of Group I doesn't differ significantly at A0 and A3 (128 +/- 11 vs 132 +/- 12 mmHg for SBP; 77 +/- 9 vs 78 +/- 7 mmHg for DBP). On the contrary, patients who develop a nephropathy see their blood pressure increase, but only SBP has a significant risk (128 +/- 12 vs 139 +/- 11 mmHg; p < 0.01). Apparition of a microalbuminuria and increase of blood pressure of Group II are not accompanied by a significant variation of serum creatinine. CONCLUSION: This study shows that for normotensive type 2 diabetic patients the transition from normo to microalbuminuria is associated with increases in systollic blood pressure. This blood pressure modification occur early, contemporary of the apparition of microalbuminuria, but relationship of causality between this two factors remains to be specified.

Adult↗
PubMed1995

Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes.

OBJECTIVES: The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias. BACKGROUND: The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration. METHODS: Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes. RESULTS: Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone. CONCLUSIONS: The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.

Analysis of Variance↗
PubMed1995

Proarrhythmic effects of a quinidine analog in dogs with chronic A-V block.

The proarrhythmic effects of 3-hydroxy-hydroquinidine (3-OH-HQ) and quinidine were compared in a canine model of QT-dependent ventricular arrhythmias. Eight hypokalemic ([K+] < or = 3.2 mmol/l) dogs with AV block (around 45 bpm) were given either drug in a randomized order at 2-day intervals. Each drug was given as two 1 hour doses, with a bolus (low dose: 5 mg/kg or high dose: 10 mg/kg) plus infusion (25 or 50 micrograms/kg/min) protocol. Propranolol infusion was combined with a third hour of the high dose infusion. Electrophysiologic measurements were performed at baseline and 30 minutes after the beginning of each dose and propranolol infusion, and proarrhythmic events were recorded 30 minutes before and during the experiment. Neither drugs altered the ventricular cycle length. Quinidine and 3-OH-HQ prolonged the QT interval similarly and significantly when paced at 60 bpm after the low dose (+39 +/- 18 and +28 +/- 22 msec, respectively) and after the high dose (+51 +/- 29 and +50 +/- 22 msec). Quinidine was more arrhythmogenic than 3-OH-HQ: 7/8 dogs (p < or = 0.05) developed ventricular arrhythmias (isolated, repetitive ventricular beats, or polymorphic ventricular tachycardias) during quinidine infusion (low dose: 4 dogs) compared to 3/8 dogs (NS) during 3-OH-HQ infusion (low dose: 1 dog). Addition of propranolol-induced bradycardia (around 30 bpm) caused torsades de pointes (wave burst arrhythmias) or polymorphic ventricular tachycardias after both drugs (in 3 dogs after quinidine and in 2 dogs after 3-OH-HQ). Thus 3-OH-HQ was slightly less arrhythmogenic than quinidine in this model of torsades de pointes, but the addition of an extra favouring factor (bradycardia) reduced that difference.

Adrenergic beta-Antagonists↗
PubMed1995

The pharmacokinetics of dexfenfluramine in obese and non-obese subjects.

The pharmacokinetics of dexfenfluramine (d-F) and its metabolite dexnorfenfluramine (d-NF) were compared in 10 obese (145 +/- 13 s.d. % of ideal body weight (IBW)) and 10 non-obese healthy volunteers (93 +/- 8% IBW). Each group included five men and five women, aged 28 +/- 8 years. Subjects were given single doses of d-F i.v. (15.5 mg base infused over 3 h) and orally (25.9 mg base in capsules) on separate occasions. After i.v. infusion in obese subjects, the volume of distribution (Vss) of d-F was significantly higher (969.7 +/- 393.3 l; 95% CI 688.6-1250 l) than in controls (668.7 +/- 139.6 l; 95% CI 568.9-768.5 l; P < 0.01). Clearance was not significantly different (43.9 +/- 21.0 l h-1 vs 37.3 +/- 10.6 l h-1) and the terminal half-life tended to be longer (17.8 +/- 9.4 vs 13.5 +/- 3.9 h NS). Combined data from the two groups indicated a positive correlation between Vss and % IBW (r = 0.544; P < 0.02). The oral bioavailability of d-F was 0.61 +/- 0.15 in obese subjects and 0.69 +/- 0.11 in controls. There was no significant difference between obese subjects and controls in Cmax, tmax and t1/2,z (Cmax: 20.1 +/- 6.7 and 27.3 +/- 6.2 micrograms l-1; tmax: 3.5 vs 3.0; t1/2,z: 16.5 +/- 7.1 vs 14.5 +/- 2.6 h respectively). The AUC ratio expressed in molar units for d-F/d-NF was 2.29 +/- 1.78 (i.v.) vs 1.25 +/- 0.64 (oral) in obese subjects and 2.05 +/- 1.26 (i.v.) vs 1.40 +/- 0.87 (oral) in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Relationships between acute and chronic beta-blocking effects of bisoprolol in healthy volunteers: a practical approach to predict intensity of beta-blockade.

Bisoprolol is a selective beta 1-adrenoceptor antagonist devoid of partial agonist activity that can be used for treatment of chronic and acute myocardial ischemia. In this condition, it is important to demonstrate that a stable beta-blocking effect at steady state can be predicted by a mathematical model determined by plasma concentration-effect relationship after an acute intravenous (i.v.) dose. This relation was studied in 10 healthy volunteers in a double-blind, randomized, cross-over, placebo-controlled study after a 5-min i.v. infusion of bisoprolol (5 mg) or placebo. Standardized exercise tests were recorded at different times for 48 h after infusion with simultaneous bisoprolol assay (high-performance liquid chromatography, HPLC) in plasma. After a 1-week interval, subjects received oral bisoprolol (10 mg once daily) for 5 days and exercise tests were repeated on day 5 before and 2, 3, and 4 h after dosing, with bisoprolol plasma level determined simultaneously. In the acute period, bisoprolol significantly decreased exercise heart rate (HR: peak effect -20.5 +/- 4%) as compared with placebo. There was a direct relationship (no hysteresis) between beta-blockade and plasma concentrations with a sigmoid (7 subjects) or a linear (3 subjects) best-fit model. After repeated bisoprolol administration, steady-state plasma levels were achieved and 88% of the observed decreases in exercise HR were within the 95% confidence interval (CI) for individual prediction. These data suggest that bisoprolol-induced beta-blockade after repeated oral dosing can be predicted by single-test i.v. dose administration.

Adult↗
PubMed1994

Determination of itraconazole and its active metabolite in plasma by column liquid chromatography.

Itraconazole is a new triazole antifungal agent. Active orally, this drug is effective against a wide range of fungal pathogens that includes Aspergillus species, and its use in leukemic and AIDS patients is currently on the increase. Oral itraconazole absorption presents up to threefold interindividual variation in man and is reduced in AIDS patients. Consequently an individual itraconazole adjusting dosage is necessary to ensure adequate clinical antifungal activity. Itraconazole undergoes extensive metabolism and the main isolated metabolite, hydroxyitraconazole, is found in plasma at concentrations 2-3-fold higher than parent drug and presents in vitro the same antifungal activity. At present, despite the contribution of this metabolite to the overall activity of the drug, no well-documented assay was reported in the literature for the codetermination of itraconazole and hydroxyitraconazole in plasma. Due to the wide variety of coadministered drugs to patients receiving itraconazole, the purpose of the developed method was to obtain a specific assay sensitive enough for itraconazole therapeutic monitoring. Therefore, a three-step liquid-liquid extraction procedure following by reversed-phase chromatography and spectrofluorimetric detection was performed. This assay allowed determination of 20 ng/ml of both itraconazole and its active metabolite with an acceptable precision using a 0.5-ml plasma sample; no analytic interference was encountered from 45 coadministered drugs tested.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Cyclosporine in whole blood: drug monitoring difficulties and presentation of a reliable normal-phase liquid chromatographic assay.

Monitoring of cyclosporine (CsA) in whole blood is complicated by the important intra- and interindividual variabilities in its pharmacokinetics and by its narrow therapeutic range. Consequently, an individual CsA adjusting dosage is necessary to ensure adequate immunosuppression without major toxic effects. This can be achieved by several methods of drug determination, including immunoassays and high-performance liquid chromatography (HPLC). Despite the use of specific monoclonal antibodies, immunoassays tend to overestimate (at least slightly) CsA blood levels due to a certain percentage of cross-reactivity with drug metabolites; so, at the present time, HPLC remains the reference method. The main problems of CsA analysis by liquid chromatographic (LC) methods depends on its physicochemical properties: a low detection wavelength and the need to use the LC column at a high temperature. A sensitive assay for the determination of CsA in whole blood has been developed using C8 solid-phase column extraction followed by normal-phase LC of the sample. This assay allowed determination of 25 ng/ml CsA in whole blood with an acceptable precision (intra- and interassay variabilities ranged from 7.7 to 10.4%, respectively n = 5). Standard curves constructed daily over the concentration range 25 to 400 ng/ml showed good reproducibility [coefficient of variation (CV) = 5.3%; n = 5] and the assay was linear up to 1,000 ng/ml. A chromatographic run was achieved in 5 min and no late eluting peak was observed. This method has proven to be reliable from the French interlaboratory cyclosporine quality assessment scheme and has been used routinely over 2 years to determine residual blood concentrations of liver transplant recipients.

Chromatography, Liquid↗
PubMed1993

Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination.

1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-blind, randomised cross-over four-period protocol. Subjects received nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a combination of both drugs and placebo during 5.5 days. Steady-state pharmacokinetics of nicardipine and metoprolol were analyzed. Beta-adrenoceptor blockade was assessed as the reduction of exercise-induced tachycardia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in subjects of the poor metaboliser phenotype than in extensive metabolisers. Beta-adrenoceptor blockade was also more pronounced in poor metabolisers than in extensive metabolisers of dextromethorphan during treatment with metoprolol alone or in combination with nicardipine (24.0 +/- 2.4% vs 17.1 +/- 3.5% and 24.1 +/- 2.5% vs 15.4 +/- 2.7% reduction in exercise trachycardia, respectively, P < 0.01 in each case). 4 Nicardipine produced a small increase in plasma metoprolol concentration in extensive metabolisers from 35.9 +/- 16.6 to 45.8 +/- 15.4 ng ml(-1) (P < 0.02), but had no significant effect in poor metabolisers. However, nicardipine did not alter the R/S metoprolol ratio in plasma 3 h after dosing, the plasma concentration of S-(-)-metoprolol 3 h after dosing or the beta-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to alpha-hydroxy-metoprolol was not altered significantly in extensive metabolisers. Plasma nicardipine concentration and beta-adrenoceptor blocking effects did not differ between the phenotypes and were not influenced by metoprolol. We conclude that beta-adrenoceptor blockade during repeated dosing with metoprolol is more pronounced in poor than in extensive metaboliser subjects, that nicardipine decreases a CYP2D6-independent route of metoprolol elimination but does not increase beta-adrenoceptor blockade during repeated dosing with metoprolol.

Adrenergic beta-Antagonists↗
PubMed1993

Antiarrhythmic effect of a sotalol-mexiletine combination on induced ventricular tachycardia in dogs.

Mexiletine was recently shown to antagonize the effects of sotalol on repolarization of canine Purkinje fibers. The significance of this interaction for the antiarrhythmic properties of these drugs remains unknown. The antiarrhythmic effects of sotalol and mexiletine alone and in combination on induced ventricular tachycardias (VTs) were assessed in 20 conscious dogs with chronic infarction. Electrophysiological measurements and programmed stimulation were performed before and after the infusion of sotalol (4 mg/kg) or mexiletine (4 mg/kg), and after infusion of the combination. The electrophysiological parameters didn't change after mexiletine. Sotalol alone and the combination both similarly prolonged the QT interval and VERP. Induction of VT by programmed stimulation was not prevented by mexiletine, but the cycle length of monomorphic VT was increased in 7 of 10 dogs. The induction of VT was prevented by sotalol (11/16 dogs), but VTs were not slowed significantly. Sotalol plus mexiletine prevented VT as did sotalol alone (11/16 dogs). The combination also increased the cycle length of VT in all eight dogs with monomorphic VT. Thus, the antagonism shown in vitro appears to have no consequences in this model. On the contrary, the sotalol-mexiletine combination showed some additive antiarrhythmic effects on induced VT in dogs.

Animals↗
PubMed1992

Prediction of sotalol-induced maximum steady-state QTc prolongation from single-dose administration in healthy volunteers.

The relationship between racemic sotalol plasma concentrations and QTc interval prolongation after both single-dose and repeated administration of three sotalol oral doses was studied in a randomized crossover protocol performed in 10 healthy volunteers. QTc interval increase was significant after the three single-dose sotalol administrations and was significantly related to the administered dose (p < 0.0001). In 21 of 30 analyses, QTc interval was linearly correlated with sotalol plasma concentrations. After the 320 mg dose, the linear model was a best fit for 90% of the cases, and no hysteresis was observed. After repeated sotalol administration, 69 of 87 QTc interval measurements at steady state could be predicted from the plasma concentration versus effect relationship established after single-dose 320 mg administration. Seventeen of 18 errors (94%) corresponded to QTc intervals that were significantly lower than predicted. These findings suggest that a short-term individual linear model determined after a 320 mg test dose of sotalol allows a good prediction of expected maximal increase in QTc duration in healthy subjects.

Administration, Oral↗
PubMed1992

Rapid and sensitive liquid chromatographic assay of mefenamic acid in plasma.

Mefenamic acid (MA) is a nonsteroidal antiinflammatory analgesic agent widely used clinically. A simple and sensitive liquid-chromatographic assay has been developed for the quantitative determination of MA in human plasma. A reverse phase, 10-microns cyano column (25 x 0.4 cm), a mobile phase of water-acetonitrile-methanol-17 M acetic acid (69:15:15:1 by volume), and an ultraviolet detection (290 nm) are used for the separation of MA and internal standard (methyl-clonazepam). MA and internal standard are extracted from acidified plasma into diethyl ether and after evaporation of the organic phase, the residue is redissolved in methanol. Calibration curves are linear in the range 0.05-3.20 micrograms/ml, and at the plasma level corresponding to the quantification limit (0.05 microgram/ml) coefficients of variation are 7.5% and 10.2% for repeatability and reproducibility studies, respectively. This assay was successfully used in the study of pharmacokinetics of MA in human plasma after a single oral administration of a low MA dose.

Carbamazepine↗